Acyl substituted indane carboxylic acids

ABSTRACT

Acyl substituted indane carboxylic acids, e.g., 5-pivaloyl-2indan carboxylic acid, are prepared by hydrolyzing and decarboxylating a 5-pivaloylindan-2,2-dicarboxylic acid diethyl ester, and are useful as hypolipidemic agents.

United States Patent 1 1 Houlihan et al.

ACYL SUBSTITUTED INDANE CARBOXYLIC ACIDS Inventors: William J. Houlihan, Mountain Lakes; Jeffrey Nadelson, Lake Parsipanny, both of NJ.

Assignee: Sandal-Wander, lnc., Hanover, NJ.

Filed: Aug. 31, 1973 Appl. No.1 393,475

U.S. Cl. 260/515 R, 260/475 SC, 260/592,

424/317 Int. Cl. C07c 65/20 Field of Search 260/515 R References Cited UNITED STATES PATENTS 2/1972 .luby et a]. 260/469 Mar. 11, 1975 OTHER PUBLICATIONS Chem. Abstracts, Vol. 12, (1918), p. 144.

Askam et al., J. Chem. Soc., (I954), pp. 4691-4693.

Primary Eruminer-James A. Patten Attorney, Agent, or FirmGerald D. Sharkin; Robert 5. Honor [57] ABSTRACT 3 Claims, N0 Drawings 1 2' ACYL SUBSTITUTED INDANE CARBOXYLIC lyzed employing conventional techniques e.g., with an ACIDS alkali metal base such as socium or potassium hydrox- This invention relates to acyl substituted indane caride, the latter being especially preferred, followed by boxylic acids which exhibit hypolipidemic activity. In acidification and spontaneous decarboxylation using an particular, it relates to alkanoyl substituted indane car- 5 aqueous mineral acid in the presence of an aqueous solboxylic acids, pharmaceutically acceptable salts, their vent. Suitable acids which can be employed include preparation and intermediates thereof. strong mineral acids, such as hydrochloric acid, sulfuric The compounds of this invention may be represented acid and hydrobromic acid, preferably hydrochloric by the formula acid. The aqueous solvent can be water or a mixture of water and a water soluble organic solvent e.g., lower alkanols having 1 to 4 carbon atoms, e.g., methanol, ethanol and the like. The temperature of the reaction is not critical, but it is preferred that the reaction be carried out between about 60 to 180C, preferably at the reflux temperature of the solvent. The reaction is run from about 12 to 36 hours, preferably about 18 to (I) 22 hours. The product is recovered by conventional techniques, e.g. crystallization.

The compounds of formula (II), are prepared by the CO H 3 following reaction scheme: 2

CO Et CH Br CH BI CO Et 2 co ne D CH =0 I 0 31-. i R C CH R1 (I: CH3 2 R2 (III) (IV) (II) wherein R and R each independently represent alkyl 40 where D represents an alkali metal such as sodium or having 1 to 2 carbon atoms, i.e., methyl or ethyl. potassium, and

The compounds of formula (I) are prepared accord- R and R are as defined above. ing to the following reaction scheme: T e c mp nd 0f formula are pr p y CO Et COZH CO Et hydrolysis I decarboxylation f F R c ca R c-cn l 3 l I 3 (II) (I) where R, and R are as defined above. treating a compound of the formula (III) with a com- The compounds of formula (I) are prepared by hypound of the formula (IV) in the presence of a strong drolysing and decarboxylating a compound of the forbase such as sodium hydride, potassium hydride, potasmula (II). The compounds of formula (II) are hydrosium ethoxide or sodium ethoxide, the latter being especially preferred. The reaction is carried out in the bled from the carotid arteries. Serum or plasma sampresence of an inert organic solvent such as the lower ples are collected, and 1.0 ml. samples of the serum are I alkanols, e.g., methanol, ethanol and the like, dimethyladded to 9.0 ml. redistilled isopropanol. Two autoanaformamide or dimethylacetamide, preferably ethanol. lyzer cupsful of a mixture of zeolite-copper hydroxide The temperature of the reaction is not critical, but it is 5 and Lloydds reagent (Kessler, E., and Lederer, H., preferred that the reaction be run from about to 1965, Technicon Symposium Mediad Inc., New York, 30C., preferably about C. The reaction is run from (345-347) are added, and the mixture is shaken for about 12 to 24 hours, preferably about 16 to 20 hours. one hour Cholesterol and triglyceride levels are deter- The product is recovered using conventional techmined simultaneously on the same sample by Techniniques, e.g. crystallization. 10 con N24 A (cholesterol) and N-78 (triglyceride) meth- The compounds of formula (III) are prepared acodology. The mean total serum cholesterol levels are cording to the following reaction scheme: then computed and the hypocholesterolemic activity is CH CH Br brominating agent ::o *0 l l-c CH R CH R 2 where R, and R are as defined above. expressed as the fall in cholesterol levels as a a percent- The compounds of formula (III) are prepared by age of the control level. The change in serum triglycertreating a compound of formula (V) with a brominatide levels induced by the drug is computed as a pering agent in the presence of an inert organic solvent centage of the control triglyceride levels. and free radical initiator. The brominating agent which For such usage, the compounds (I) may be combined can be used is bromine, N-bromosuccinimide, N- with a pharmaceutically acceptable carrier or adjuvant bromophthalamide, N-bromoacetamide and the like. and may be administered orally or parenterally as such The particular agent used is not critical, but N- or admixed with conventional pharmaceutical carriers. bromosuccinamide is preferred. In the preferred pro- They may be administered in such forms as tablets, discess, the free radical initiator used is an organic peroxpersible powders, granules, c psul y p and eliXerS ide, especially benzoyl peroxide. The reaction can also and parenterally as solutions, suspensions, dispersions, be carried out under ultraviolet light. Although the paremulsions and the like, e.g. a sterile injectable aqueous ticular solvent used is not critical, the preferred solsolution. The dosage will vary depending upon the vents are the halogenated hydrocarbons such as m thmode of administration utilized and the particular comylene dichloride, chloroform, carbon tetrachloride and pound employed. I

the like, although the aromatic hydrocarbons such as The COmPOImdS of formula y be slmllarly qbenzene can also be employed. The temperature of the ministered in the form of their non-toxic pharmaceutireaction is not critical, but reflux temperature of the cally acceptable salts. Such salts possess the same order solvent is preferred. The reaction is run for about 12 to of activity as he free s and are readily P p y 48 hours; preferably about 18 to 25 hours. The product reacting the base with an appropriate hydroxide or is recovered by conventional techniques, e.g., crystalli- 50 oxide and, accordingly, are included within the scope zation. of this invention. Representative of such salts are the Many of the compounds of formula (V) are knownalkali metal salts, e.g., sodium, potassium andthe like, and may be prepared by methods described in the literthe alkaline earth metal salts such as magnesium, calature. The compounds of formula (V) not specifically cium and the like. disclosed may be prepared by analogous methods from The hypolipidemic effective dosage of compounds known starting materials. (I) employed in the alleviation of lipidemia may vary The compounds of formula (1) are useful because depending on the particular compound employed and they possess pharmacological activity in animals as the severity of the condition being treated. However, in hypolipidemic agents, particularly as hyperlipogeneral, satisfactory results are obtained when the proteinemic agents as indicated by the fall of cholescompounds of formula (1) are administered at a daily terol and triglyceride levels in male albino Wistar rats dosage of from about 4.0 milligrams to about 250 milliweighing 1 10-130 g. initially. The rats are maintained grams per kilogram of animal body weight, preferably on drug-free laboratory chow diets for seven days and given in divided doses two to four times a day, or in susthen divided into groups of 8 to 10 animals. Each group tained release form. For most large mammals, the total with the exception of the control is then given orally 30 daily dosage is from about 300 milligrams to about milligrams per kilogram of body weight per diem of the 3000 milligrams. Dosage forms suitable for internal use compound for six days. At the end of this period, the comprise from about to about 1500 milligrams of animals are anesthetized with sodium hexobarbital and the active compound in intimate admixture with a solid Ingredients Weight (mg) 5-pivaloyl-2-indan carboxylic 150 acid insert solid diluent (starch, 300

lactose, kaolin.)

EXAMPLE 1 a,a-dibromo-4-pivaloyl-o-xylene To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of a solution of 2.6 g. (1.17 mole) 4-bromo-o-xylene in 650 ml. dry tetrahydrofuran, the reaction is started and the remainder of the bromoxylene is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 1% hours. The resulting grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at to 5C. The solution is stirred for an additional 1% hours at 0 and then at room temperature for 18 hours. The mixture is then cooled to 0 and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloride acid, 100 ml. percent sodium bicarbonate solution and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed vacuo to give 4-pivaloyl-oxylene (b.p. 143/12mm). A mixture of the resulting 4-pivaloyl-o-xylene is then added to 31.0 g. (1.77 mole) N-bromosuccinimide, 4.0 g. (0.016 mole) benzoyl peroxide and 1000 ml. of carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting precipitate is washed with carbon tetrachloride. The solvent is removed in vacuo and the residue is crystallized from petroleum ether to give a, a-dibromo-4-pivaloyl-o-xylene, m.p. 65-68.5C.

EXAMPLE 2 pivaloyl-o-xylene in 120 m1. dry tetrahydrofuran while maintaining the temperature at 30C. The resulting mixture is stirred at room temperature for 20 hours. Water is added and the excess ethanol is removed in vacuo, and the resulting residue partitioned between water and ether. The resulting layers are washed with water, and brine, decolorized with charcoal, dried over anhydrous magnesium sulfate, and evaporated. The residue is distilled at l190/0.5mm to give 5- pivaloylindan-Z,2-dicarboxylic acid diethyl ester, m.p.

EXAMPLE 3 S-pivaloyl-Z-indan carboxylic acid A mixture of 20.1 g (0.06 mole) of 5-pivaloy1indan- 2,2-dicarboxylic acid diethyl ester, and 16.8 g (0.3 mole) of potassium hydroxide in ml. of ethanol and 90 ml. of water is refluxed for 3 hours. The solvent is then evaporated in vacuo and the aqueous base solution is extracted with ether, decolorized, cooled to 0C. and then acidified with 250 ml. of concentrated hydrochloric acid and refluxed for 18 hours. The resulting solution is cooled and extracted with ether. The ether is then washed with 2N sodium hydroxide and the basic water is decolorized, and made acidic at 0C. with concentrated hydrochloric acid, extracted with ether, and the ether is then dried and evaporated. The resulting residue is recrystallized from pertroleum ether to give S-pivaloyl-Z-indan carboxylic acid, m.p. l 1 l1 12.5C.

The 5-piva1oyl-2-indan carboxylic acid of this example is an effective hypolipidemic agent when orally administered to an animal suffering from lipidemia at a dosage of mg. four times per day.

What is claimed is:

1. A compound of the formula CO H indan carboxylic acid.

each independently represent alkyl 

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compound of claim 1 in free acid form. 